Sarcoidosis: clinical update REVIEW U. Costabel

Copyright #ERS Journals Ltd 2001
European Respiratory Journal
ISSN 0904-1850
ISBN 1-904097-01-4
Eur Respir J 2001; 18: Suppl. 32, 56s–68s
Printed in UK – all rights reserved
REVIEW
Sarcoidosis: clinical update
U. Costabel
Sarcoidosis: clinical update. U. Costabel. #ERS Journals Ltd 2001.
ABSTRACT: Many advances have been made regarding sarcoidosis in the past 2
decades. As a result, sarcoidosis is now defined as a multisystem disorder with a heightened cellular immune response at sites of disease activity in patients with a predisposition for sarcoidosis and a presumed exposure to as yet unknown transmissible
environmental agents.
Recent International Consensus Statement recommendations regarding diagnosis and
therapy have been published. The diagnosis of sarcoidosis is based on a compatible
clinical and/or radiological picture, histological evidence of noncaseating granulomas
and exclusion of other diseases capable of producing a similar histological or clinical
picture.
Therapy is based on corticosteroids, although there are indications of valuable
alternatives. Except for life- and sight-threatening organ involvement, it should be
carefully considered whether the patient might benefit from treatment. For asymptomatic pulmonary sarcoidosis, a watch and wait approach is appropriate; treatment
should mainly be considered if symptoms develop or lung function deteriorates.
Eur Respir J 2001; 18: Suppl. 32, 56s–68s.
Sarcoidosis has been characterized for over a
century, initially through its skin manifestations, and
later, with the use of routine and screening chest
radiography, as a frequently asymptomatic disease
with hilar lymphadenopathy and pulmonary infiltration. The disease is an immunological disorder
par excellence, involving many components of the
immune system. With the introduction of bronchoalveolar lavage (BAL) as a major research tooly20 yrs
ago, the characteristic features of a heightened cellular
immune response at sites of disease activity have been
identified. Previously, sarcoidosis had been misinterpreted as an immune deficiency disease with depressed
cellular immunity because of the cutaneous anergy.
The descriptive definition of sarcoidosis, as reported
at the World Congress in Kyoto in 1991 [1], reads
as follows: "Sarcoidosis is a multisystem disorder
of unknown cause. It commonly affects young and
middle-aged adults and frequently presents with
bilateral hilar lymphadenopathy, pulmonary infiltration, ocular and skin lesions. Other organs may also
be involved. The diagnosis is established when clinicoradiological findings are supported by histological
evidence of noncaseating epithelioid cell granulomas.
Granulomas of known causes and local sarcoid
reactions must be excluded. Frequently observed
immunological features are depression of cutaneous
delayed-type hypersensitivity and increased CD4/CD8
ratio at the site of involvement. Circulating immune
complexes along with the signs of B-cell hyperactivity
may also be detectable. The course and prognosis may
correlate with the mode of the onset and the extent
of the disease. An acute onset with erythema nodosum
Correspondence: U. Costabel, Ruhrlandklinik, Dept Pneumology/Allergology, Tueschener Weg 40, 45239 Essen,
Germany.
Fax: 49 2014334029
Keywords: Bronchoalveolar lavage
CD4/CD8 ratio
corticosteroids
Löfgren9s syndrome
sarcoidosis
or asymptomatic bilateral hilar lymphadenopathy
usually heralds a self-limiting course, whereas an insidious onset, especially with multiple extra-pulmonary
lesions, may be followed by relentless progressive
fibrosis of the lungs and other organs."
It is evident that many immunological features are
part of this definition. After briefly discussing the
current understanding of epidemiology, aetiology and
immunology, this review mainly focuses on the
present diagnostic approach to and management of
the disease, taking into account new advances related
to sarcoidosis. Importantly, for the first time in the
history of sarcoidosis, a Consensus Statement by
the American Thoracic Society (ATS), the European
Respiratory Society (ERS), and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) has recently been published to
update clinicians and scientists on the disease, and
to help in the management and care of patients, by
giving recommendations regarding diagnosis and
therapy [2].
Epidemiology
Significant heterogeneity in prevalence, disease presentation and severity of sarcoidosis occurs among
different ethnic and racial groups and in various
countries. The prevalence ranges from less than one
case to 40 cases per 100,000. The highest prevalence
rates, withw50 cases per 100,000, have been reported in
Scandinavian countries and the US African-American
population [3]. Sarcoidosis is common in Central
SARCOIDOSIS: CLINICAL UPDATE
Europe, USA and Japan. It appears less frequently in
Central and South America, other Asian countries
and Africa. Sarcoidosis in African-Americans is more
severe, while Caucasians are more likely to present
with asymptomatic disease. Overall mortality is 1–5%
[2]. In Japan, the most frequent cause of death in sarcoid patients is from myocardial involvement, whereas
respiratory failure is more common elsewhere.
Erythema nodosum associated with acute disease
and good prognosis is the presenting symptom in
18% of Finnish and 30% of British sarcoidosis
patients, whereas it is very rare in African-Americans
and the Japanese [3, 4]. In contrast, lupus pernio
and other cutaneous manifestations are associated
with a chronic course and appear more frequently in
African-Americans than in Caucasians [3]. Spatial and
familial clustering of sarcoidosis may occur. This may
indicate shared exposure to an environmental agent or
a genetic predisposition for the disease expression.
Sarcoidosis shows a predilection for adults v40 yrs,
peaking between 20–29 yrs. There is a slight female
predominance. In Scandinavian countries, Germany
and Japan, there is a second peak incidence in females
w50 yrs of age [2]. Sarcoidosis rarely occurs in
children and the elderly.
Aetiology
The aetiology is still unknown, although there has
been an intensive search for possible aetiological
agents. The general concept has emerged that sarcoidosis results from the exposure of genetically susceptible individuals to specific environmental agents.
There are several lines of evidence supporting this
concept, which are outlined in more detail in the
Report of Working Group 2 by VERLEDEN et al. [5] in
this Supplement.
57s
308 in the promoter region. One of its alleles, the
TNFA2 allele, is linked to elevated TNF-a levels.
However, a recent study showed no association
between the expression of this allele and an exaggerated release of TNF-a in sarcoidosis patients, casting
some doubt on its pathogenetic relevance [12]. Also,
the TNF-a genotype is not associated with susceptibility to sarcoidosis. A shift to the TNFA2 allele was
observed only in the subgroup of patients with
Löfgren9s syndrome, not the entire sarcoidosis
cohort [13].
Another polymorphism of potential relevance is
found in the angiotensin converting enzyme (ACE)
gene [14, 15]. Although the polymorphism influences
the serum ACE levels (the DD (deletion) genotype
being associated with high, the ID (insertion/deletion)
genotype with intermediate, and the II (insertion/
insertion) genotype with the lowest levels), most
studies failed to show an association between the
ACE genotype and the risk of developing sarcoidosis
[16–18]. Other studies showed such an association
with the DD genotype only in African-Americans
[19] or reported an increased frequency of the DD
genotype only in sarcoidosis patients with autoimmune manifestations [20]. Furthermore, only one
study has found the ACE DD genotype to be associated with a poorer prognosis than the other
genotypes [21].
Vitamin D receptor gene polymorphisms have
recently been investigated, and the B allele has been
suggested to be a genetic risk factor for sarcoidosis
[22]. For more detailed insights into the complex
issues of genetic components in sarcoidosis, the reader
is referred to an exhaustive review on this topic
recently published in this journal [23] and to the Report
of Working Group 2 by VERLEDEN et al. [5] in this
Supplement.
Exposure to transmissible environmental agents
Sarcoid constitution
There is familial clustering of sarcoidosis [6]. In
Ireland, 2.4% of sarcoidosis cases occur among
siblings [7]. The most common relationship is between
brother and sister, followed by mother and offspring.
A genetic predisposition may explain the heterogeneity in disease presentation and severity among
different ethnic and racial groups. The human leukocyte antigen (HLA)-type A1/B8/Cw7/DR3 carries a
good prognosis and correlates with acute disease,
including Löfgren9s syndrome, whereas chronic disease is associated with B13 in Japanese subjects and
BW15 in African-Americans. In a Scandinavian
study, DR17 was associated with a better pulmonary
function, a good prognosis and short disease duration.
In contrast, DR14 and DR15 were related to a more
prolonged disease course [8–11]. The HLA-B22
phenotype is associated with disseminated systemic
disease in Italians [9].
Gene polymorphisms of proinflammatory cytokines
may also be associated with the expression of the
disease. One such bi-allelic polymorphism is found in
the tumour necrosis factor (TNF)-a gene at position
Immunological abnormalities in sarcoidosis are
characterized by features of an antigen-triggered cellmediated immune response. The pattern of cytokine
production in the lungs is most consistent with a Th1type immune response [11, 24–26].
Seasonal clustering of sarcoidosis in the early
spring, spatial clustering in the Isle of Man, and
work-related clustering in nurses and other healthcare
workers are consistent with the concept of an infectious cause of the disease [2]. In addition, sarcoidosis
can be transmitted via transplanted organs: recipients
of cardiac or bone marrow transplants from sarcoidosis patients have subsequently developed sarcoidosis
[27].
Several infectious organisms have been implicated
as possible agents in the aetiology of sarcoidosis,
e.g. viruses (human herpes virus, retrovirus, EpsteinBarr virus (EBV)), bacteria (Propionibacterium
acnes, Borrelia burgdorferi, Mycoplasma, Chlamydia,
Nocardia), and mycobacteria (Mycobacteria tuberculosis, Mycobacteria paratuberculosis, cell wall deficient
mycobacteria) [2, 11, 28]. Serological studies have
detected increased serum antibodies against several of
58s
U. COSTABEL
these agents, but this probably reflects an epiphenomenon due to increased polyclonal immunoglobulin
production by the hyperactive B-cell system, rather
than a specific response to a causative agent.
Unfortunately, even with the advent of molecular
tools, there is no definite proof of a specific infectious
aetiological agent in sarcoidosis: no infective or other
agent has been consistently isolated or cultured.
Immunopathogenesis
Immunological abnormalities are characterized by
the accumulation of activated CD4z T-cells of the
Th1-type and macrophages at sites of ongoing
inflammation, notably in the lung [11, 25, 26, 29].
Cytokines and other mediators produced by these
cells contribute to granuloma formation. Macrophages show enhanced expression of major histocompatibility complex (MHC)-class-II and other
costimulatory accessory molecules. The elevated
accessory function is mainly mediated by the expression of CD54 and CD80 [30, 31]. The enhanced
antigen presenting capacity of macrophages is probably induced by interaction with the potential
sarcoidosis antigen or antigens. These alveolar macrophages recognize, process and present the putative
antigen to Th1 lymphocytes. The activated sarcoid
macrophages produce interleukin (IL)-12, a key
cytokine in inducing the shift towards a Th1 profile
and stimulating interferon (IFN)-c production by
lung T-cells [32–36]. The activated T-cells in turn
release IL-2 and chemotactic factors for blood
monocytes, leading to further recruitment of monocytes/macrophages to the site of disease activity. IFNc is able to further activate macrophages, and IL-2
activates and expands the various T-lymphocyte
clones [37–40]. IFN-c is also important for the transformation of macrophages into giant cells (macrophage fusion factor), which are important building
blocks of the granuloma [41]. The proinflammatory
macrophage cytokines IL-1, IL-6 and TNF-a are
essential to induce and maintain granuloma formation, and all are increased in sarcoidosis [42], whereas
the anti-inflammatory cytokine IL-10 is not increased
in sarcoidosis [32, 43]. However, controversial results
regarding its messenger ribonucleic acid (mRNA)
expression by BAL cells have been reported [32, 33].
The role of transforming growth factor (TGF)-b is
also still controversial. One study found high TGF-b
release from BAL cells in active disease undergoing
spontaneous remission [43], whereas another group
reported increased BAL levels in patients with altered
lung function [44].
Activated macrophages are able to secrete various
fibroblast growth factors. They probably contribute to
fibroblast proliferation, collagen synthesis, and development of fibrosis in sarcoidosis, although this last
step in the pathogenesis, the passage from granuloma
to fibrosis, is not well understood. No studies have
shown why lung disease persists in some patients but
not in others. No studies have shown how persistent
disease results in lung injury and fibrosis. A shift from
a Th1 to a Th2 phenotype with secretion of IL-4
and IL-10 may be important for persistent disease,
whereas the Th1 cytokines are likely to favour the
granulomatous response [26]. Definitive longitudinal
data on lung Th1 and Th2 response in patients with
pulmonary sarcoidosis are lacking. Studies of the
different phases (early alveolitis, granuloma, fibrosis)
are needed to understand the regulatory immune
mechanisms that govern the outcome of the disease.
Since the first report by MOLLER et al. [45] on a bias
in the usage of certain T-cell antigen receptors (TCR)
by T-cells in the lungs of sarcoidosis patients, numerous studies have confirmed the existence of T-cells
that have a restricted TCR repertoire in involved
tissues [46]. A preferential usage of TCR Vb2 and/or
Vb8 has been reported. One study showed a strong
association between the HLA-DR17 haplotype and
the expression of TCR Va2.3 by CD4z lung T-cells
[47]. There was also a relationship between Va2.3z
CD4z T-cells in BAL and clinical signs of disease
activity [47]. A bias in the usage of certain TCR genes
indicates oligoclonal proliferation of T-cells, which
may be consistent with stimulation of T-cells by an
antigen or a superantigen. Since T-cells in BAL from
healthy individuals have not shown a preferential
expression of particular TCR regions, the bias found
in the lung in sarcoidosis would indicate that T-cells
have been exposed to an antigen that is not normally
present. It is still unclear, however, how helpful TCR
studies will be in eliciting the aetiology of sarcoidosis.
Clinical presentation
Because sarcoidosis is a multiorgan disorder,
patients may present to clinicians of different specialities. The clinical picture is very variable and
depends on ethnicity, duration of illness, site and
extent of organ involvement, and activity of the
granulomatous process, which shows a tendency to
wax and wane.
There are three different modes of clinical presentation: asymptomatic sarcoidosis; nonspecific constitutional symptoms; and symptoms related to specific
organ involvement. The true numbers of asymptomatic patients cannot be reliably determined, since
many of them escape diagnosis. These patients are
usually detected by abnormal routine chest radiograph. In various series, 30–50% of patients were
found to be asymptomatic at the time of diagnosis
[48–49].
Constitutional symptoms are present in about onethird of patients, and more frequently in AfricanAmericans. The symptoms include fever (generally
low-grade but up to 40uC has been observed), weight
loss (usually limited to 2–6 kg during the 10–12 weeks
prior to presentation), fatigue and weakness, which
can be disabling [50], and drenching night sweats [51].
Sarcoidosis should always be included in the differential diagnosis of fever of unknown origin.
The frequency of clinical findings related to the
involvement of specific organs is variable, depending
on how thoroughly the diagnostic investigations
explore the extent of organ involvement (table 1).
There are two different types of onset in sarcoidosis
SARCOIDOSIS: CLINICAL UPDATE
Table 1. – Organ involvement in sarcoidosis
Organ
% of patients
Mediastinal lymph nodes
Lungs
Liver
Spleen
Eyes
Peripheral lymph nodes
Skin
Nervous system
Heart (clinically)
95–98%
w90%
50–80%
40–80%
20–50%
30%
25%
10%
5%
patients. 1) Acute sarcoidosis has an abrupt onset, is
more frequent in Caucasians than African-Americans,
and may present as Löfgren9s Syndrome, which is
characterized by bilateral hilar adenopathy, ankle
arthritis, erythema nodosum, and frequently constitutional symptoms including fever, myalgia, malaise and
weight loss [52]. The prognosis is good and spontaneous remission usually occurs within 2 yrs. Rarely,
erythema nodosum may relapse, even after many
years. 2) Chronic sarcoidosis has an insidious onset.
Organ-related symptoms, often related to pulmonary
infiltration, such as cough and dyspnoea, predominate, whereas constitutional symptoms are much rarer
than in the acute form. The course is often relapsing,
with resolution being less likely and taking a more
protracted time course than in the acute form.
Organ manifestations
Lungs
The lungs are affected in w90% of patients.
Prominent symptoms are dyspnoea, dry cough, and
chest pain, occurring in 30–50%. Haemoptysis is rare.
In contrast to many other interstitial lung diseases,
clubbing and fine crackles are not usually present
[53]. There is a higher incidence of sarcoidosis in
nonsmokers [54].
The chest radiograph types are shown in table 2. In
type I disease, without radiological involvement of the
lung parenchyma, biopsy can still reveal granulomata in the lung tissue in up to 80% of patients. A
unilateral, and then mostly left-sided hilar lymph node
enlargement, is extremely rare. Calcified hilar lymph
nodes may occur in 5% of patients and are a sign of
long-standing sarcoidosis, resembling the eggshell
calcification described in silicosis. The most common
type of lung infiltrate is diffuse with an interstitial
Table 2. – Chest radiographic stages of sarcoidosis
Stage
0
I
II
III
IV
Frequency
Normal
BHL
BHL and parenchymal infiltrates
Parenchymal infiltrates without BHL
Signs of fibrosis
BHL: bilateral hilar lymphadenopathy.
5–10%
50%
25%
15%
5–10%
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reticulonodular pattern and upper lobe predominance. Areas of consolidation, even with associated
air bronchograms, may also be present. Type IV
disease represents the fibrotic stage, with shrinking of
mainly the upper lobes, together with hilar retraction,
deformity of the parenchymal structures with pleural
adhesions to the diaphragm, bulla formation, cysts
and honeycombing. Larynx, trachea and bronchi may
also be involved, leading to stridor, airway obstruction and bronchiectasis. The incidence of bronchial
hyperreactivity is increased. Pleural effusion, pneumothorax, severe pleural thickening are uncommon
manifestations [55].
Lymphoid system
Peripheral lymph nodes are enlarged in about onethird of patients and they may offer a good site for
biopsy [56]. The spleen is frequently involved, in
40–80% of autopsy studies, but clinical symptoms
due to splenomegaly (local pressure, haematological
abnormalities due to hypersplenism) are rare [57]. A
very unusual complication of massive splenomegaly is
splenic rupture (spontaneous or traumatic).
Skin
Cutaneous involvement occurs in about onequarter of the patients [58]. This is less frequent and
usually less severe in Caucasians than in AfricanAmericans. There are a number of skin manifestations
ranging from small purplish papules to plaques and
subcutaneous nodules. Small maculopapular eruptions may disappear during the course of the disease,
whereas other lesions tend to wax and wane, including
the unique variant of scar sarcoidosis. Lupus pernio is
an indurated, bluish discoloration of the nose, cheeks,
lips or ears, and usually heralds a poor prognosis.
Erythema nodosum is a manifestation of acute sarcoidosis that is not associated with the presence of
granulomas and usually subsides within 6–8 weeks.
In this regard, biopsy of an erythema nodosum lesion
is not useful, whereas other skin manifestations
are good, noninvasive biopsy sites for granuloma
demonstration.
Ocular involvement
Ocular lesions occur in 20–30% of patients and are
most serious because of the threat of blindness [59].
Since eye involvement may be asymptomatic, every
patient with sarcoidosis should undergo ophthalmological investigation, including slit lamp examination.
The chronic form of uveitis may lead to glaucoma,
cataract and blindness. Any part of the eye may be
involved, but the most common lesion is uveitis. Acute
anterior uveitis resolves spontaneously or after local
therapy with corticosteroids, whereas posterior uveitis
needs systemic treatment.
60s
U. COSTABEL
Heart
Clinical heart involvement occurs in 5% of patients,
but the autopsy incidence may be much higher [60].
Sudden death may occur. The main manifestations are
arrythmia of all types, conduction abnormalities, and
congestive heart failure [61]. If a conventional electrocardiogram (ECG) shows any abnormality, 24-h
Holter monitoring should be performed. Dopplerechocardiography may show cardiac dysfunction, especially diastolic dysfunction, in which case
Thallium-201 (201Tl)-scintigraphy is indicated. 201Tl
accumulates in normal myocardial cells. Segmental
areas of decreased Tl uptake correspond to granulomata or fibrosis. In contrast to perfusion defects of
cardiac ischaemia, the defects in sarcoidosis decrease
in size during exercise. This phenomenon is called
reversed distribution [62]. Coronary angiography is
needed to exclude the possibility of coronary artery
disease if myocardial sarcoidosis is suggested by
201
Tl-imaging. Endomyocardial biopsy has a low
sensitivity of v50%. Thus, a sarcoidosis patient with
ECG abnormalities and/or cardiac dysfunction and
201
Tl-imaging defects should be presumed to have
cardiac involvement, even in the absence of a positive
myocardial biopsy, and should be treated accordingly.
formed in many other disorders. Occasionally, liver
involvement is severe, leading to intrahepatic cholestasis, portal hypertension and hepatic failure, so that
treatment is indicated.
Other organ involvement
Cystic bone lesions are rare and almost exclusively
associated with chronic skin lesions. Joint pains occur
in 25–39% of patients, but deforming arthritis is rare.
Muscle involvement may cause proximal weakness.
Corticosteroid-induced myopathy should be excluded.
Renal involvement in sarcoidosis may result from
hypercalcaemia/hypercalciuria, causing nephrocalcinosis, urolithiasis, and renal failure, and also from
direct involvement of the kidneys by a granulomatous
interstitial nephritis. Haematological abnormalities
are rarely severe. Leukopenia occurs in as many as
40% of patients. The most likely mechanism is a
redistribution of blood T-cells to the site of the
disease. The most frequent endocrine manifestation is
hypercalcaemia, occurring in 2–10%. Diabetes insipidus may occur as a result of pituitary or hypothalamic
involvement [2, 66].
Diagnostic approach
Nervous system
Neurological manifestations occur in v10% of
patients [61, 63]. There is a predilection for the base
of the brain. Some lesions tend to occur early and
respond favourably to treatment. These include
cranial nerve involvement, particularly facial palsies,
and hypothalamic and pituitary lesions. In contrast,
space-occupying masses, peripheral neuropathy and
neuromuscular involvement occur later and are associated with a chronic course. One problem in making
the diagnosis is the difficulty of obtaining histological
proof. Frequently, the diagnosis of nervous system
involvement rests on clinical features, together with
demonstration of sarcoidosis in other organs and
exclusion of other neurological diseases. Computed
tomography (CT) and magnetic resonance imaging
(MRI) are indicated in patients with neurological
symptoms and signs. Gadolinium (Gd)-enhanced
MRI may reveal involvement of brain parenchyma,
meninges and spinal cord. MRI manifestations are,
however, nonspecific. Cerebrospinal fluid reveals
lymphocytosis, elevated protein and increased ACE.
The triad of facial nerve palsy, parotitis and anterior
uveitis is called Heerfordt syndrome and carries a
good prognosis.
Liver involvement
This is usually clinically mild, with an asymptomatic increase in hepatic enzymes [64, 65]. The liver is
palpable in only y20% of patients. In contrast,
granulomata on liver biopsy are found in up to 80%
of patients. However, the liver should not be the site
of first choice biopsy, since liver granulomas are
The diagnosis of sarcoidosis is based on the
following criteria: 1) a compatible clinical and/or
radiological picture; 2) histological evidence of noncaseating granulomas; and 3) exclusion of other
diseases capable of producing a similar histological
or clinical picture.
In suspected sarcoidosis, the diagnostic procedures
should attempt to accomplish the following four
goals: 1) provide histological confirmation of the
disease; 2) assess the extent and severity of organ
involvement; 3) assess whether the disease is stable or
likely to progress; and 4) determine if the patient will
benefit from therapy.
Biopsy procedures
The site for biopsy is dependent on the manifestation of the disease. Historically, biopsies of scalene
lymph nodes or mediastinoscopy were often performed. Nowadays, transbronchial lung biopsy
through a fibreoptic bronchoscope is the recommended
procedure in most cases [2]. In experienced hands, the
diagnostic yield is high, reaching 80–90% if ¢4–5
adequate samples are obtained [67]. Even in stage I
disease, the yield may be 70–80% [68]. Bronchial
mucosal biopsy should also be taken, since the histological demonstration of granuloma is possible in
40–60% of cases, even when the bronchial mucosa is
grossly normal. When gross endoscopic findings such
as mucosal nodularity, oedema or hypervascularity
are present, the yield of endobronchial biopsies may
exceed 90% [69]. These bronchoscopic biopsy procedures may be combined with BAL and studies
of lymphocyte subpopulations. Three independent
SARCOIDOSIS: CLINICAL UPDATE
groups have shown very similar values for the
sensitivity and specificity of BAL CD4/CD8 ratios
[70–72]. A ratio of w3.5 or 4.0 has a sensitivity of
52–59% and a specificity of 94–96%. These three
studies reached a similar conclusion: in patients with a
clinical picture typical of sarcoidosis, an elevated
CD4/CD8 ratio in BAL may confirm the diagnosis
and obviate the need for confirmation by additional
biopsy [73]. It is important to note that in the study of
WINTERBAUER et al. [71], transbronchial biopsy had a
specificity of 89% for the distinction between sarcoidosis and other forms of diffuse lung disease, and was,
therefore, no better than the CD4/CD8 ratio in this
regard.
Other possible sites for biopsy are visible skin
lesions, the lips (minor salivary gland involvement),
the conjunctiva, or superficial lymph nodes, if they are
enlarged. Biopsy of erythema nodosum lesions is not
useful as they do not show granulomas. In general, the
easiest accessible biopsy site is the target for biopsy
confirmation. Biopsy of the liver is nonspecific and
not recommended. If bronchoscopic biopsies or BAL
have failed and no other easily accessible sites are
identified, mediastinoscopy or surgical lung biopsy
may be indicated.
The basic histopathological lesion in sarcoidosis is
the noncaseating epithelioid cell granuloma. This
consists of radially arranged epithelioid cells, which
are surrounded by a lymphocytic infiltration. Multinucleate giant cells of the Langhans9 type are present
and may contain Schaumann and asteroid bodies.
These granulomas may resolve spontaneously, leaving
no scar, or may persist for a long time and may finally
undergo hyalinization and fibrosis, which usually
begins at the periphery and travels to the centre of
the granuloma. This may lead to a loss of tissue
architecture. In the lungs, the granulomas are located
close to or within the connective tissue sheath of the
bronchioles, subpleural and perilobular spaces, and
small vessels (a lymphangitic distribution).
The patient without biopsy
Some patients refuse biopsies. In others, lung
biopsy may be associated with an increased risk.
Clinical and radiological findings alone are highly
reliable in patients with stage I disease (accuracy,
98%). The diagnostic reliability in stage II disease is
also good (89%) but it is less reliable for patients with
stage III (52%) or stage 0 (23%) disease [74].
In this regard, a recent risk/benefit and cost/benefit
analysis in presumptive stage I sarcoidosis showed
that observation of a patient with bilateral hilar
lymphadenopathy (BHL), presenting without symptoms and with normal physical examination is
absolutely justified [75]. Estimates based on the US
incidence rates of sarcoidosis came to the following
conclusions: if 33,000 persons with asymptomatic
BHL underwent mediastinoscopy, 32,982 (99.95%)
would be diagnosed with sarcoidosis I, eight with
tuberculosis, nine with Hodgkin9s disease, and one
with non-Hodgkin9s lymphoma. The benefit of the
avoidance of two additional deaths due to the late
61s
diagnosis of malignant lymphoma would be highly
offset by the number of complications: 407 patients
would require hospitalization, 204 would experience
major morbidity, and the costs would be 100–200
million US dollars [75]. In another classical study of
100 consecutive patients with BHL, w95% of asymptomatic individuals with BHL and normal physical
examination had sarcoidosis [49]. Malignancies were
the cause of sarcoidosis in 11 of 100 patients, and all
were symptomatic. Therefore, histological confirmation may not be needed in asymptomatic patients who
have symmetric BHL. However, when the BHL is
asymmetric, massive or associated with large paratracheal enlargement, biopsy confirmation is strongly
advised.
In patients with the classical Löfgren9s syndrome,
biopsies are usually not necessary. If a Gallium (67Ga)
scan is available, the simultaneous demonstration of
a lambda pattern (i.e. 67Ga uptake in bilateral hilar
and right paratracheal lymph nodes) and a panda
pattern (uptake in parotis and lacrimal glands) may
be sufficient for diagnosis, but the sensitivity of this
combination for sarcoidosis is low, only 13–48% [76,
77]. A CD4/CD8 ratio in BAL w3.5 may support the
diagnosis of sarcoidosis. The Kveim-Siltzbach test is
no longer available in most countries due to availability of tissue, difficulties in standardizing and
validating the preparation, and risks of transmission
of infective diseases.
Additional investigations
At the initial diagnostic evaluation, a number of
tests are strongly recommended as routine procedures
for all patients (table 3) [2]. Pulmonary function tests
only have a modest correlation with the chest radiograph. They are even important in patients without
pulmonary signs and symptoms to provide a baseline
for detection of improvement or deterioration of lung
involvement during the further course of the disease.
Only 20% of patients with stage I disease show abnormalities in pulmonary function tests, compared with
40–70% in the other radiographic stages [55]. The
Table 3. – Recommended tests for initial evaluation of
sarcoidosis
Type of evaluation
History (occupational and environmental exposure,
symptoms)
Physical examination
Postero-anterior chest radiography
Pulmonary function tests: spirometry and carbon
monoxide diffusion capacity
Peripheral blood counts: white blood cells, red blood cells,
platelets
Serum chemistries: calcium, liver enzymes, creatinine,
blood urea nitrogen
Urine analysis
Electrocardiography
Routine ophthalmologic examination
Tuberculin skin test
62s
U. COSTABEL
most sensitive tests are the diffusion capacity and the
vital capacity tests. As well as a restrictive impairment,
an obstructive lung function pattern is seen in up to
30% of patients, and bronchial hyperreactivity is
present in y25% of patients. Blood testing is performed to exclude hypercalcaemia and significant
hepatic, renal, or haematological involvement. Routine ophthalmological investigation, including an initial slit lamp examination, is obligatory in all patients
in order to exclude a clinically silent uveitis.
Chest CT is not routinely needed. In some patients
(according to the author9s experience, y30% of
patients), high-resolution CT (HRCT) is indicated
for the following reasons: atypical clinical and/or chest
radiographic findings; a normal chest radiograph
but a clinical suspicion of the disease; suspected complications of lung disease, such as bronchiectasis,
aspergilloma, pulmonary fibrosis, and traction emphysema; or a superimposed infection or malignancy.
Apart from hilar and mediastinal adenopathy [78],
the characteristic findings of sarcoidosis on HRCT are
nodular infiltrates with a bronchovascular and subpleural distribution, thickened interlobular septa,
architectural distortion, and conglomerate masses
originating from coalescence of nodules in the
perihilar, peribronchovascular or subpleural regions.
Less common findings are honeycombing, cyst formation and bronchiectasis, and ground-glass opacities or alveolar consolidation. In a similar manner
to the conventional chest radiographic findings,
lung CT does not correlate well with the functional
impairment.
Specific investigations are needed if extrapulmonary
sarcoidosis is suspected. These have been discussed in
the Organ manifestations section.
Assessment of activity
A long list of laboratory and cell biological markers
have been discussed as potential indices of active
disease [29, 79–81], either in serum (e.g. ACE, lysozyme, neopterin, soluble IL-2-receptor, soluble intracellular adhesion molecule (ICAM)-1, IFN-c) or in
BAL fluid (e.g. high lymphocytes, activation marker
expression on T-cells, CD4/C8 ratio, macrophage
TNF-a release, collagenase, procollagen-III-peptide,
vitronectin, fibronectin, hyaluronan). However, none
of them can be recommended for routine assessment,
perhaps with the exception of serum ACE [82]. The
serum ACE only has a limited value in diagnosing
sarcoidosis, but it is useful in monitoring the course of
disease. Serum ACE is elevated in 40–90% of patients
who have clinically active disease. The likely sources
of the circulating enzyme are activated epithelioid cells
and macrophages at sites of inflammation. Thus,
elevated serum ACE levels probably reflect the total
body granuloma burden and do not necessarily reflect
disease activity in the lungs. They seem to correlate
broadly with the number of organs involved and the
number of extrapulmonary sites. The magnitude of
the initial ACE levels has no prognostic significance
and the initial levels are no different between patients who deteriorate and those who improve. After
initiation of treatment, serum ACE levels can be
helpful in monitoring the treatment effect, since
increased serum ACE activity will usually be reduced
within a few weeks of the start of corticosteroid
treatment. In the future, revised normal ranges,
corrected for the ACE genotype, might improve the
clinical significance of this marker [18].
At present, the best way to assess the activity of
sarcoidosis is still through clinical activity. This is
based on the mode of onset, the worsening or persistence of symptoms, and the presence of skin lesions,
in combination with changes in chest radiography and
lung function tests, with or without treatment.
Natural history and prognosis
The clinical course is highly variable in sarcoidosis,
with a tendency for the disease to wax and wane,
either spontaneously or in response to therapy. One
characteristic feature of sarcoidosis is the high rate of
spontaneous remission, globally seen in 60–70% of
patients, whereas a chronic course is seen in only
10–30%, depending on geographical and ethnic
differences [2, 48, 58, 66, 83–85]. The prognosis is
best in acute onset disease, e.g. Löfgren9s syndrome.
Severe extrapulmonary manifestation (e.g. heart, central nervous system, liver) is seen at initial presentation in only 4–7% of patients, but this percentage
increases with longer disease duration. Permanent
sequelae will be experienced by 10–20% of patients.
Sarcoidosis can generally be considered as a benign
disease with a good prognosis. Sarcoidosis-related
mortality is low: only 1–5% of patients die from their
disease, most frequently from respiratory insufficiency, neurosarcoidosis or cardiac involvement.
Larger series show that 30–50% of all patients require
treatment with corticosteroids at some time in their
disease course [2, 58, 66]. Several clinical features have
been associated with a chronic or progressive course
(see table 4) [2, 58, 86].
Many studies have shown that the chest radiographic stages provide useful prognostic information.
In fact, no modern biological marker in serum or BAL
has been proven to better the conventional chest
radiographic staging system in this respect. Spontaneous remission occurs in [2, 84–86]: stage I in
55–90%; stage II in 40–70%; stage III in 10–30%;
Table 4. – Adverse prognostic factors in sarcoidosis
Type of factor
Lupus pernio
Chronic uveitis
Age at onset w40 yrs
Chronic hypercalcaemia
Nephrocalcinosis
Black race
Progressive pulmonary sarcoidosis
Nasal mucosal involvement
Cystic bone lesions
Neurosarcoidosis
Myocardial involvement
SARCOIDOSIS: CLINICAL UPDATE
and stage IV in 0–5%. These remissions are usually
seen after 1–3 yrs. Those patients who spontaneously
remit or stabilize show late relapses in only 2–8%
of cases [87–89]. Failure to regress spontaneously
within 24 months predicts a chronic or persistent
course.
The clinical follow-up investigations should include
physical examination, chest radiography, serial lung
function measurements, and other organ-specific tests
if specific organs are involved. For stage I disease,
initial follow-up every 6 months is usually adequate;
more frequent evaluation (every 3–6 months) is
advised for stage II, III, or IV sarcoidosis. All patients
should be monitored for a minimum of 3 yrs after
therapy is discontinued. Subsequent follow-up is not
required unless new or worsening symptoms develop,
or extrapulmonary sites are involved. By contrast,
patients with persistent, stable disease should be
followed over a long period of time, sometimes indefinitely. This also applies to patients with serious
extrapulmonary involvement. Patient surveillance
needs to be more vigilant after corticosteroid-induced
remissions because of the high rate of relapse in
this context, ranging from 14–74% (table 5) [48, 84,
87–90]. A recent study showed that there were no
relapses if patients remained asymptomatic for 3 yrs
after prednisone withdrawal [90].
Treatment
The appropriate treatment has not been well
defined for all patients. Because of the variable
course of sarcoidosis and the fact that the majority
of patients undergo spontaneous remission, indications for therapy are still controversial and the optimal dose and duration of corticosteroids has not been
adequately studied in randomized, prospective trials.
Extrapulmonary involvement
Systemic corticosteroids are clearly indicated for
life- or sight-threatening organ involvement, i.e. cardiac or central nervous disease, or ocular disease not
responding to topical therapy. Other indications for
therapy include persistent hypercalcaemia, persistent
renal dysfunction, severe hepatic dysfunction with
portal hypertension or icterus, palpable splenomegaly or evidence of hypersplenism, severe fatigue
and weight loss, dysfiguring skin lesions, or chronic
myopathy [2, 66, 86].
Table 5. – Intervals and duration of follow-up for sarcoidosis
Stage I disease: every 6 months
Other stages: every 3–6 months
Follow-up for a minimum of 3 yrs after therapy is
discontinued
If radiograph has normalized for 3 yrs, subsequent
follow-up is not routinely required
Follow-up needs to be more vigilant after corticosteroidinduced remissions than after spontaneous remission.
63s
Pulmonary sarcoidosis
Although the overall effectiveness of corticosteroids
in changing the long-term outcome of sarcoidosis is
unclear, it is well known that corticosteroids provide
acute symptomatic relief and reverse organ dysfunction in patients with symptomatic pulmonary disease.
It is obvious that treatment of the cause of sarcoidosis
is not possible due to unknown aetiology. The aim of
treatment can only be to prevent irreversible loss of
function of the involved organs and to improve symptoms, if they are severe and affecting the patient9s
quality of life. Obviously, the natural course of the
disease, e.g. the time point when the natural disease
activity resolves by the elimination of the causative
agent, cannot be influenced by corticosteroids. Most
physicians feel that progressive symptomatic pulmonary disease should be treated. It is less clear whether
persistent pulmonary infiltrates or mildly abnormal
lung function require therapy. Indications for observation are asymptomatic patients who have normal
lung function and patients who have minimal, welltolerated symptoms and only mild, functional abnormalities, until they experience disease progression
[2, 88]. This approach is supported by two recent
studies, as outlined here.
HUNNINGHAKE et al. [88] performed a prospective
study of 91 previously untreated patients with sarcoidosis, in which they limited the use of corticosteroids
to patients that had objective evidence of recent
deterioration in lung function or serious extrapulmonary disease. According to these criteria, 36 were
treated with corticosteroids and 55 were observed
without therapy. Of these, only eight deteriorated,
eventually required corticosteroids and responded to
this therapy. Of the 36 patients who were treated with
corticosteroids, 20 remained stable and 16 improved
clinically.
In the British Thoracic Society study [87], 58
sarcoidosis patients who, in the first 6 months after
entry to the study, neither required prednisolone for
symptoms nor showed radiographical improvement,
were randomly allocated at 6 months to receive either
long-term steroid treatment for ¢18 months, or were
treated only selectively if later symptoms developed or
lung function deteriorated. In the long-term treatment
group, vital capacity improved from an initial value
of 89% predicted to a final value of 99% pred.
Importantly, in the selective treatment group, vital
capacity remained stable, from 89–92%. On average,
there was no deterioration in lung function. In
addition, only six of 31 patients in the selective
treatment group required therapy during follow-up
because of symptoms or deterioration of lung function. The author believes that the message from this
study is to wait and treat only if symptoms develop or
lung function deteriorates.
For pulmonary sarcoidosis, the initial prednisone
dose is generally 20–40 mg?day-1: higher doses may be
needed for cardiac or neurological sarcoidosis. The dose
is slowly tapered to 5–10 mg?day-1 over 2–3 months.
Alternate day treatment using equivalent total
dosages is also effective in maintaining improvement
and may decrease the side-effect of hypothalamic
64s
U. COSTABEL
suppression, but not the side-effects of osteoporosis
and cataract formation. Treatment should be continued for a minimum of 12 months [2, 91]. Patients
with Löfgren9s syndrome do not require therapy with
corticosteroids because their symptoms usually respond well to nonsteroidal anti-inflammatory drugs.
Patients need to be followed for relapse after dose
reduction or discontinuation of therapy. Some patients who have repeated relapses may require indefinite
therapy.
Alternative drugs
Several cytotoxic agents have been used to treat
patients requiring long-term corticosteroid therapy
and suffering from major side-effects. Usually, these
drugs are combined with corticosteroids and are
used in order to lower the dose of steroids, but in
some selected cases they may be given as single
therapy. On the basis of safety and efficacy, methotrexate (10–25 mg?week-1) and azathioprine (100–
150 mg?day-1) are the preferred agents [92–96]. Both
have minimal-to-no carcinogenicity with the doses
used in sarcoidosis. Cyclophosphamide and chlorambucil should be reserved for refractory cases (table 6)
[2].
The antimalarial drugs chloroquine and hydroxychloroquine have been used as first-line drugs for
lupus pernio, nasal sarcoidosis, other disfiguring
sarcoid skin disease, and hypercalcaemia [97–99]. A
recent report indicated the efficacy of chloroquine
and hydroxychloroquine in the treatment of neurosarcoidosis after failure of corticosteroid therapy or
unacceptable side-effects with corticosteroids [100].
The response rates are higher with chloroquine than
with hydroxychloroquine, but hydroxychloroquine is
less toxic and may be used for prolonged periods
without retinal damage, making it the preferred drug
to chloroquine [99, 100]. Chloroquine treatment is
best limited to a 6-month period. Recently, chloroquine has also been shown to be effective in chronic
pulmonary sarcoidosis [101].
There is anecdotal experience that suggests that
pentoxyfylline is beneficial when used alone or with
corticosteroids in the treatment of sarcoidosis [102].
This is probably due to its inhibitory effect on alveolar
macrophage TNF-a release [103]. Until further study
results become available, pentoxifylline therapy still
has to be considered as experimental. Thalidomide
may be considered as another corticosteroid-sparing
option in the treatment of sarcoidosis [104]. Cyclosporine has been shown to have no clinical effectiveness for pulmonary sarcoidosis, despite experimental
evidence that suggests that it suppresses the T-helper
cell activity in the lungs [105, 106].
With the availability of specific antagonists against
TNF-a in the treatment of rheumatoid arthritis,
this approach may also be considered in the future
for the rare cases of chronic sarcoidosis, refractory to
corticosteroids and other immunosuppressive and
cytotoxic agents.
Topical corticosteroid therapy
Topical therapy with corticosteroids can be sufficient for some patients with skin sarcoidosis, nasal
involvement, iritis/uveitis, or airway disease. Inhaled
corticosteroids may reduce symptoms in endobronchial sarcoidosis, such as cough and airway hyperreactivity. The role of inhaled corticosteroids in the
treatment of parenchymal pulmonary sarcoidosis is
still uncertain. Several recent studies have shown that
this therapy has some benefits, but the effects are
modest and generally involved groups of patients with
mild disease and good prognosis [107, 108]. Other
studies failed to show clinical efficacy [109, 110]. In a
recent study of inhaled fluticasone in adults with
stable sarcoidosis, there was no improvement in any
physiological outcome measure [111].
Associated conditions and complications
Patients who have advanced fibrocystic sarcoidosis
may develop bronchiectasis and mycetomas. Both
complications may give rise to life-threatening haemoptysis [66, 112]. Surgical resection and embolization of the bronchial arteries have been reported as
helpful in selected cases. Systemic antifungal agents
are not recommended since no clinical trials have
demonstrated efficacy. Usually, haemoptysis is the
result of associated bronchiectasis and bronchitis, and
responds to conservative therapy with bedrest, cough
suppression, antibiotics and increased corticosteroid
Table 6. – Alternative drugs for sarcoidosis
Toxicity*
Nausea
Mucositis
Haematological
Teratogenic
Carcinogenic
Other
Drug and dosage
Methotrexate
10–25 mg?week-1
Azathioprine
50–200 mg?day-1
Cyclophosphamide
50–150 mg?day-1
Hydroxychloroquine
200–400 mg?day-1
1
2
1
2
0
Liver, lung
2
1
2
1
1
Liver
3
1
3
3
3
Bladder
1
0
0
0
0
Retinal
*: 0=none; 1=minimal; 2=occasional problem; 3=significant problem; it may be necessary to adjust the dosage or to use other
agents.
SARCOIDOSIS: CLINICAL UPDATE
doses [66]. In these cases, maintenance low-dose
corticosteroids may be helpful in minimizing repeated
episodes of haemoptysis.
In end-stage pulmonary sarcoidosis and cor pulmonale, supplemental oxygen, diuretics and bronchodilators for obstructive impairment are indicated. Lung
and other organ transplantation has been successfully performed in sarcoidosis [113, 114]. Although
recurrent sarcoid lesions are common in the lung
allograft, fortunately, this is not clinically or radiographically relevant. Survival is comparable to other
lung transplant recipients [114].
Osteoporosis is a potential complication in patients
who are treated with corticosteroids. Since sarcoidosis
may induce hypercalciuria and hypercalcaemia by
increased endogenous vitamin D production, patients
should be monitored closely when vitamin D or
calcium is supplemented for osteoporosis prevention
[115]. Calcitonin and bisphosphonates have been
shown to reverse steroid-induced osteoporosis in
sarcoidosis patients [116].
6.
7.
8.
9.
10.
11.
12.
Outlook
In the past 2 decades, many advances have been
made in gaining a better understanding of the pathogenesis, the incidence and prevalence of the disease,
and some genetic factors, which may define patients
with a distinct phenotype and prognosis. Making
a diagnosis with less invasive procedures is also
understood.
However, many issues of clinical management and
understanding of disease development in individual
patients are still unclear. The new millennium will
probably provide answers to the following questions:
whether there is an early test to predict disease
progression and prognosis; if there are less toxic
therapies than corticosteroids or cytotoxic agents;
which genetic factors increase susceptibility to the
disease; how genes modify the expression of the
disease; what mechanisms lead to persistent disease
and development of fibrosis; and which agent(s) cause
sarcoidosis.
13.
14.
15.
16.
17.
18.
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